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Endocannabinoids (anandamide and 2-AG) are relevant modulators of appetite and energy expenditure through their action on cannabinoid CB(1) receptors. The actions of anandamide on feeding behavior are dependent both, on the anatomical location of CB(1) receptors (central nervous system versus peripheral tissues) and the feeding status. Anandamide uptake into cells, prior to its degradation by specific enzymatic systems, is a necessary step for the regulation of its extracellular levels. The present study explores the route and feeding stimulus dependency of the effects of the anandamide uptake blocker AM404. Peripherally, AM404 reduced feeding in partially satiated animals through a PPARα-independent mechanism, but not in food deprived ones. When AM404 was injected into the cerebral ventricles of food deprived rats, it resulted in hyperphagia that was antagonized by the cannabinoid receptor inverse agonist SR141716A. These results support the multimodal action of endocannabinoid signaling in feeding regulation, which depends on the anatomical site and the feeding status of the animal., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In an attempt to establish a relationship between food intake and fear/anxiety-related behaviours, the goal of this study was to investigate the effect of bilateral injections of GABAA (Muscimol, MUS, doses 25 and 50ng/side) and GABAB (Baclofen, BAC, doses 32 and 64ng/side) receptor agonists in the nucleus accumbens shell (AcbSh) on the level of fear/anxiety-like and feeding behaviours in 24h food-deprived rats. The antagonists of GABAA (Bicuculline, BIC, doses 75 and 150ng/side) and GABAB (Saclofen, SAC, doses 1.5 and 3μg/side) were also tested. The results indicated that the total number of risk assessment behaviour decreased after the injection of both doses of GABAA agonist (MUS) into the AcbSh of 24h food-deprived rats exposed to elevated plus maze. Similar results were obtained after treatment with both doses of GABAB (BAC) agonist in the AcbSh. These data indicated that the activation of both GABAA and GABAB receptors within the AcbSh caused anxiolysis in 24h food-deprived rats. In addition, feeding behaviour (food intake, feeding latency and feeding duration) remained unchanged after treatment with both GABA agonists. In contrast, both food intake and feeding duration decreased after injections of both doses of BIC (GABAA antagonist), while the feeding latency remained unchanged after treatment with both GABA antagonists in the AcbSh of 24h food-deprived rats. The treatment with SAC (GABAB antagonist) did not affect feeding behaviour. Collectively, these data suggest that emotional changes evoked by pharmacological manipulation of the GABA neurotransmission in the AcbSh are not linked with changes in food intake., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Previous research has demonstrated that administration of μ-opioid receptor agonists into the nucleus accumbens increases high-fat diet consumption in sated rats and has shown a role of basolateral amygdala (BLA) activity in mediating this response. The present experiments were conducted to examine the role of BLA opioid transmission in mediating high-fat feeding driven by either intra-accumbens opioid activation or 24-h home cage food deprivation. Injection of the μ-opioid agonist, d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) into the nucleus accumbens (0.25μg/0.5μl/side) increased consumption of a high-fat diet, and this effect was attenuated by pre-treatment with the opioid antagonist, naltrexone (5μg/0.25μl/side) administered into the BLA. In contrast, intra-BLA naltrexone administration had no influence on the increase in high-fat intake following 24-h food deprivation. These findings suggest that BLA opioid transmission is an important mediator of palatability-driven feeding as modeled by intra-accumbens opioid activation, while BLA opioid transmission has no significant influence on the increase in high-fat feeding driven by short-term negative-energy balance., (Copyright © 2010. Published by Elsevier Inc.)

Bupropion has been found to be a useful pharmaceutical agent in furthering smoking abstinence. Preclinical research investigating the effects of bupropion on nicotine self-administration has indicated bupropion has selective effects on nicotine self-administration. However since response rates maintained by nicotine were significantly lower than rates of response maintained by the non-drug reinforcers, bupropion may have resulted in rate-dependent effects. The current experiments attempted to decrease the high response rate maintained through non-drug reinforcers in order to have more comparable control rates when investigating the selectivity of bupropion for nicotine self-administration. The effects of bupropion on nicotine self-administration (0.03 mg/kg/inf) were compared to food-maintained responding at two levels of food deprivation (deprived and satiated). Rats were satiated prior to the experimental session in order to decrease the overall response rates maintained through food reinforcement. Bupropion increased nicotine intake, but dose-dependently decreased food intake, when rats were food-deprived. However, when more comparable rates of behavior in the food-satiated group were investigated, bupropion had similar effects on nicotine and food-maintained responding. The data indicate that the effects of bupropion can be influenced by the control rate of responding. The results from these experiments also indicate that bupropion may not exert a selective effect on nicotine self-administration, since low rates of food and drug maintained responding were increased by the drug. These results indicate the importance of controlling for differences in response rates when attempting to assess the effects of drugs on responding maintained by different reinforcers. Furthermore, the results from the present study suggest that motivational variables (i.e. food deprivation) may be used to control for response rate differences maintained by drug and non-drug reinforcers.

Substantial evidence implicates the lateral hypothalamus (LH) in the control of ingestive behavior and previous studies have found that glutamate release within the LH increases during meals. It is not known, however, whether this effect is selective for feeding, or whether similar changes are also seen during drinking. In this work, we examined this question using low-flow push-pull perfusion which allows sampling from small tissue volumes. Presentation of highly palatable solid or liquid foods to food-deprived rats resulted in an immediate increase in glutamate output of more than 200% over baseline. The response was maximal immediately after food presentation. In contrast, significant changes in glutamate output were not seen when water was presented to water-deprived animals, despite the occurrence of vigorous drinking. These findings confirm reports of feeding related glutamate release in the LH and demonstrate that this effect is specific to feeding, rather than being a general concomitant of all ingestive behaviors. The push-pull technique described here may allow the relevant region of the LH to be identified with greater precision than other methods.

Food intake is normally influenced by a multitude of complex endogenous neurochemical systems, in addition to numerous external environmental stimuli, including olfaction. Since most olfactory neurons process odorant exposures through Ca2+-mediated mechanisms via Ca2+ channels, a novel approach at influencing the ingestive behaviors of animals might therefore involve altering olfactory acuity via Ca2+ channel blockade. We tested the ability of a Ca2+ channel blocker, diltiazem, to alter food intake in hyperphagic rats when administered using the intranasal (i.n.), intraperitoneal (i.p.), oral (p.o.) or intracerebroventricular (i.c.v.) routes of administration. Male Sprague Dawley rats, which had been food-deprived for 4 h at the beginning of the dark cycle, were administered different doses of diltiazem (0-8 mg/animal or 0-40 mg/kg) and the amounts of food consumed were measured. While food intake at 1, 2 and 4 h post drug administration was significantly decreased in a dose-dependent manner after i.n. administration, the i.p., p.o., and i.c.v. routes did not affect food intake. In another experiment, rats trained to eat their daily meal during the first 4 h at the onset of the dark cycle and treated daily with i.n. diltiazem (0-8 mg/animal) prior to food introduction exhibited a significantly decreased rate of weight gain in a dose-dependent manner over a 14-day period. Both i.n. and i.p. diltiazem significantly increased the plasma drug concentration at 1 h, however there was no significant difference between these routes of administration. Additional studies failed to demonstrate any detrimental effects of i.n. diltiazem (0-8 mg/animal) on conditioned taste aversion, locomotion or gross neurological/behavioral competence using the rota-rod test. While a local action on the nasal odorant receptors is most likely the site of diltiazem's action, further studies are needed to determine the exact mechanism of action of i.n. diltiazem.

The purpose of this study was to determine how stimuli paired with food alters the effects of pharmacological and dietary manipulations on food intake. Responding of baboons was studied using a schedule of reinforcement that simulated food 'seeking' and food 'taking'. Under one condition, responding during the initial seeking component was reinforced by flashing lights that were paired with food delivery during the latter-taking component. Under another condition, responding during seeking components was reinforced by a 1-s time out that was paired with food delivery during the latter-taking component. Dexfenfluramine (DFEN) decreased responding within seeking and taking components under both conditions. Diazepam (DZP) increased responding within seeking and taking components under both conditions. Amphetamine (AMPH) increased responding within seeking components under the flashing-light condition, but did not alter responding within seeking components under the 1-s time-out condition. AMPH decreased responding within taking components under both conditions. As observed with AMPH, caloric prefeeding also increased responding within seeking components only under the flashing-light condition. As observed with DZP, acute deprivation also increased responding within seeking and taking components under both conditions. The effects of AMPH and caloric prefeeding on food seeking are dependent upon the type of stimuli, paired with primary reinforcement.

Giving L-tryptophan, serotonin's circulating precursor, or a serotonin-releasing drug can decrease food intake and body weight. Giving 5-hydroxy-L-tryptophan (5-HTP), serotonin's immediate intracellular precursor, has been thought to be ineffective in enhancing brain serotonin synthesis unless it is coadministered with a dopa decarboxylase inhibitor to protect 5-HTP from destruction outside the brain. We have examined the effect of 5-HTP on food consumption and tissue 5-HTP levels among rats subjected to two different hyperphagic stimuli, food deprivation and a standardized stress (tail pinch), and on plasma 5-HTP levels in humans. In rats, 5-HTP (3-200 mg/kg ip) suppressed food intake in a dose-dependent manner in both models, but was at least eight times more effective in our stress-hyperphagia model. (Differences in the two procedures might have contributed to the observed differences in potencies.) This suppression was blocked by coadministration of another large neutral amino acid (LNAA), L-valine. Brain 5-HTP levels correlated significantly with peak plasma 5-HTP (r(2)=.69) or 5-HTP/LNAA (r(2)=.81) levels. Additionally, among humans, oral 5-HTP (1.2-2.0 mg/kg) produced, after 1 and 2 h, a significant increase in plasma 5-HTP (1.5- to 2.3-fold). These observations suggest that 5-HTP may be useful in controlling the excessive food intake sometimes generated by stress, even if given without decarboxylase inhibitors or other drugs.

In a prior study, ad libitum fed rats learned a strong preference (90%) for a flavored saccharin solution (conditioned stimulus, CS+) paired with concurrent intragastric (IG) infusions of 5% ethanol over another flavor (CS-) paired with water infusions in unlimited access sessions (22 h/day). The present study expanded the investigation of ethanol-conditioned preferences to limited access sessions (30 min/day). Experiment 1 revealed that ad lib or food-restricted rats failed to develop a CS+ preference using the same CS solutions (0.05% Kool-Aid+0.2% saccharin) and IG infusions that were effective with long-term training. Experiments 2 and 3 mimicked the parameters from a report of successful ethanol conditioning in deprived rats: ethanol (0.5 g/kg) or water was infused intragastrically 5 min before access to sweetened CS solutions flavored with HCl or NaCl. Rats learned to prefer the ethanol-paired CS+ when the flavors were mixed with 5% sucrose but not when mixed with 0.2% saccharin. Experiment 4 revealed that 5% sucrose solutions flavored with 0.25% Kool Aid also supported flavor preference conditioning by IG ethanol (0.5 g/kg). CS+ preferences were obtained in rats trained with ethanol infused 5 min before or concurrent with CS+ intake, but not in rats trained with ethanol infused 30 min before CS+ intake. These data confirm that flavor preferences can be conditioned by IG ethanol using a limited access procedure. However, in contrast to 22 h/day training, 30 min/day training requires more intense CS flavors and a nutritive sweetener. The preference reinforcing actions of ethanol may develop slowly and are thus most effective with long training sessions or when intense CS flavors are used in short training sessions.

Opioid and dopamine systems are both implicated in the response to sweet solutions. Our laboratory previously reported that the opioid antagonist, naltrexone, reduced the intake of sweet solutions, yet had little or no effect on sucrose-conditioned flavor preferences in sham-feeding rats. The present study examined the role of dopamine D(1) and D(2) receptors in the expression of flavor preferences conditioned by the sweet taste of sucrose. All sessions were conducted under sham-feeding conditions to minimize postingestive influences. Training was accomplished by adding a novel flavor (CS+) to a 16% sucrose solution, a different flavor (CS-) to a less-preferred 0.2% saccharin solution in alternating, one-bottle sessions. Preferences were assessed in two-bottle tests with the CS+ and CS- flavors presented in mixed sucrose (8%)-saccharin (0.1%) solutions following systemic doses of 0, 50, 200, 400, or 800 nmol/kg of the D(2) antagonist, raclopride (Experiment 1) or the D(1) antagonist, SCH23390 (Experiment 2) under either food-restricted or unrestricted conditions. Rats significantly preferred the CS+ solutions in vehicle tests, and displayed equipotent and dose-dependent reductions in total intake and CS+ preference following either D(1) or D(2) receptor antagonism. Similar results were obtained with SCH23390 and raclopride in Experiment 3 conducted with water-restricted rats. These data indicate that dopaminergic D(1) and D(2) receptors play pivotal and functionally equivalent roles in the expression of flavor preferences conditioned by the sweet taste of sucrose.

According to the homeostatic model, the loss of tolerance to amphetamine-induced hypophagia requires a period of unrestricted feeding in the drug-free state, which transforms the compensatory response mediating tolerance ("hyperhunger") into a functional disturbance to homeostasis. In the absence of such a disturbance, tolerance should be retained. To test this prediction, rats tolerant to amphetamine's hypophagic effect were given a 4-week tolerance retention period during which milk intakes were restricted and deprivation levels held relatively constant. During this period the rats were assigned to one of the following drug treatment conditions: 1) saline injections both before and after daily milk tests (saline group); 2) saline injections before, and amphetamine injections after, daily milk tests (after group); 3) no injections and no milk tests (no-treatment group); or 4) amphetamine injections before, and saline injections after, milk tests (before group). Despite the restricted feeding regimen, both the saline and after groups lost tolerance. These results do not support the homeostatic model, but are consistent with the instrumental learning model, which views drinking milk in the undrugged state as analogous to receiving noncontingent reinforcement.

The progressive ratio schedule provides a means to determine reinforcement value that is independent of response rate. This is achieved by increasing the number of lever presses for each successive reinforcement until, eventually, the subject fails to respond within a designated time limit. The number of responses in the final completed ratio defines the break point. When tested with appetitive gustatory stimuli (sucrose and saccharin), rats showed a concentration-dependent increase in break point when food deprived (Experiment 1A and, for sucrose only, Experiments 1B and IC) but not when water deprived (Experiment 1A). For aversive gustatory stimuli (sodium chloride, citric acid, and quinine) break point declined as concentration increased (Experiment 1A). In Experiment 1C, reinforcement duration had a significant, although relatively small, influence on break point for each of three concentrations of sucrose. Experiment 2 found a dose-dependent effect of the neuroleptic drug haloperidol (0.025, 0.05, and 0.1 mg/kg) on break point for sucrose reinforcement. The present study demonstrates that the progressive ratio schedule provides a valuable method to assess the influence of manipulations that might affect the perceived reinforcement value of gustatory stimuli.

Food deprivation increases the rewarding effects of self-administered drugs such as psychomotor stimulants and benzodiazepines. These drugs also possess aversive properties and can produce conditioned taste aversions (CTA). Because drug-seeking behavior is most likely affected by both the rewarding and aversive properties of drugs, we hypothesize that food deprivation might also attenuate a drug's aversive consequences. The CTAs induced by three different drugs (amphetamine, chlordiazepoxide, and LiCl) were assessed separately. Male Long-Evans rats were assigned to one of two feeding conditions: restricted (maintained at 80% of free-feeding body weight), or nonrestricted (with ad lib food). Both groups received CTA training, consisting of an intraoral infusion of a novel saccharin solution (10 min) followed immediately by one of two i.p. injections: paired rats received drug, and unpaired rats received a similar volume of saline. After 10 days of ad lib food access, saccharin was presented to all rats again, and the latency to reject the tastant was used as an index of CTA learning. The rats that had been food restricted at the time of conditioning exhibited attenuated CTAs relative to those that had not been deprived. These differences were seen only when a rewarding drug (amphetamine or chlordiazepoxide) and not when a nonrewarding drug (LiCl) was used as the unconditioned stimulus. In a separate experiment, we established that this effect is apparent only when the deprivation period precedes conditioning rather than precedes testing. The present results indicate that food deprivation modulates the acquisition of a CTA induced by amphetamine or chlordiazepoxide, but not LiCl.

Opioid antagonism and serotonergic stimulation is associated with macronutrient-specific hypophagia in animals. In the present study we evaluated their systemic effect alone, and in combination, at various doses, on the intake of sweet carbohydrate-rich and sweet fat-rich foods, tastes, and nutrients that are typical of binge-food items. Low-dose (1 mg/kg) naloxone, alone, preferentially suppressed fat-rich intake while low-dose (2.5 mg/kg) fluoxetine, alone, preferentially suppressed carbohydrate-rich intake. Each drug at these doses, combined with various doses of the other (2.5-10 mg/kg fluoxetine; 0.01-1 mg/kg naloxone) additively suppressed both kinds of the sweet foods. Naloxone and fluoxetine have therapeutic potential in treating binge-eating disorders. This animal study suggests what shortcomings and benefits might be expected when combining these two agents.

A multiple schedule (Mult FR 10 VI 30") was employed to examine the interaction of reinforcement schedule and food restriction on amphetamine's effects on lever pressing behavior. High response rates were observed in fixed ratio (FR) 10 components. Significantly lower response rates were observed under the variable interval (VI) 30" schedule. In the nonrestricted feeding condition, significant decreases in high rate FR 10 responding occurred after administration of 1.0 mg/kg amphetamine while lower rates under the same schedule were increased by 0.30 and 1.0 mg/kg amphetamine. In contrast, VI 30" responding was minimally effected at any amphetamine dose. Food restriction resulted in significant increases in responding in both schedule components. Under food restriction, significant decreases in responding were observed only in the FR 10 components at the highest amphetamine dose. The data indicate that amphetamine produced rate-convergent effects and the susceptibility of the animal to these effects was dependent on the schedule of reinforcement and food restriction.

The purpose of the present experiment was to replicate previously reported observations of a relationship between saccharin consumption and oral ethanol self-administration in rats using operant measures (2,8) and to determine whether saccharin intake was related to the rate of acquisition of IV cocaine self-administration. Groups of Wistar rats selected for high and low saccharin (0.1% wt/vol) intake were tested for rate of acquisition of IV cocaine (0.2 mg/kg/infusion) self-administration using an autoshaping procedure. They were subsequently tested for self-administration of oral ethanol (8% wt/vol) under ascending fixed-ratio (FR) schedules (FR 1, 2, 4, and 8). Finally, ethanol deliveries were compared under food-deprivation and food-satiation conditions under an FR 8 schedule. Saccharin intake was redetermined after each phase of the experiment. No significant differences between high and low saccharin groups were found in rate of acquisition of IV cocaine self-administration, and there was not a significant correlation between saccharin and cocaine consumption. However, the high saccharin group drank significantly more ethanol than the low saccharin group during the FR 8 food satiation component. A significant correlation between saccharin and ethanol consumption was also found. For high and low saccharin groups, responding for ethanol increased proportionally with increases in FR such that consumption of ethanol remained relatively constant as FR increased. Ethanol consumption was significantly increased under food deprivation relative to food satiation conditions for both saccharin groups. A significant correlation between ethanol consumption and cocaine consumption was also found. Significant increases in saccharin consumption across successive saccharin consumption tests were found for both groups, although relative intake for the high and low saccharin groups remained stable throughout the experiment. These results indicate that higher ethanol intake is predicted by higher saccharin intake, but saccharin intake did not predict the rate of acquisition of IV cocaine self-administration.

Effects on environmentally induced oral stereotypies (object pecking and drinker-directed activity) and other behavior (sitting, standing, pacing, preening), of preferential antagonists and agonists of central 5-HT and GABA receptor subtypes, were examined in individually caged broiler breeder fowls subjected to chronic food restriction. All drugs were injected intravenously at three doses, and their effects compared with a saline control treatment. The only significant (p < 0.05) effect of 5-HT antagonists [NAN-190 (5-HT1A), ketanserin (5-HT2), MDL-72222 (5-HT3)] was an increase in pacing with ketanserin (0.8 mg/kg). With 5-HT agonists, 8-OH-DPAT (5-HT1A) suppressed the two oral stereotypies and increased standing (all 1.0 mg/kg) and preening (0.2 mg/kg), alpha-methylserotonin (5-HT2) suppressed the oral stereotypies and increased sitting (all 1.0 mg/kg), and m-CPBG (5-HT3) suppressed drinker-directed activity (1.0 mg/kg). The GABA antagonists (bicuculline (GABAA), 5-aminovaleric acid (GABAB) had no effect, and of the GABA agonists [muscimol (GABAA), baclofen (GABAB)], muscimol suppressed preening and increased sitting, standing (all 1.0 mg/kg), and pacing (0.2 mg/kg). Most of the significant effects of serotonergic and GABAergic agents on behavior here appeared to reflect at least some degree of sedation, and there was no real evidence of any specific influence of these compounds on the oral stereotypies within the range of doses tested.

Rats that are fed for 90 min per day can stabilize their weight after an initial drop; however, if rats on this feeding schedule are also given access to a running wheel, they run excessively, eat less, lose weight, and often die. To investigate this phenomenon as a possible animal model of obsessive-compulsive disorder (OCD), rats were treated for 5 weeks with fluoxetine, an antidepressant that relieves OCD symptoms in humans (5 mg/kg, 2.5 mg/kg), or imipramine, an antidepressant that does not affect OCD symptoms (5 mg/kg), or saline prior to exposure to food restriction and the running wheel. In addition, because chronic fluoxetine treatment is thought to enhance serotonergic neurotransmission, for contrast an additional group of rats were treated with parachlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor that depletes serotonin. Rats treated with fluoxetine lost significantly less weight, ran significantly less, and increased food intake more rapidly during restriction of food availability than saline-treated rats. Rats treated with imipramine did not differ from those treated with saline on these parameters. Compared to saline-treated rats, rats treated with PCPA lost more weight, ate less food, and increased running more rapidly. These effects of pharmacological treatment indicate an inverse relationship between central serotonergic activity and vulnerability to develop food-restriction-induced anorexia and compulsive running. In addition, like OCD in humans, this phenomenon in rats seems to be blocked by chronic treatment with a serotonin selective reuptake inhibitor but not a less selective monoamine reuptake inhibitor.

We investigated whether histaminergic neurons in the brain are involved in diazepam-induced hyperphagia in rats. Pretreatment with intracerebroventricular (ICV) injection of either histamine H1-receptor antagonist, pyrilamine (10 and 30 micrograms) or histamine H2-receptor antagonist, famotidine (3 and 10 micrograms) did not affect only diazepam (1 mg/kg, subcutaneous, SC)-induced hyperphagia in nondeprived rats, but also spontaneous feeding in food-deprived rats. In addition, pretreatment with ICV injection of histamine H3-receptor antagonist, thioperamide, and histamine H3-receptor agonist, (R) alpha methylhistamine, enhanced and inhibited diazepam-induced hyperphagia (1 mg/kg, SC) in nondeprived rats, respectively. However, thioperamide and (R) alpha methylhistamine did not affect spontaneous feeding in food-deprived rats. These findings suggest that histaminergic neurons are not directly involved in diazepam-induced hyperphagia in rats. Furthermore, enhancement or inhibition of diazepam-induced hyperphagia by histamine H3-receptor antagonist or agonist may occur via histamine H3-receptors localized in the other neurons in the rat brain.

This study characterizes the cue properties of quinpirole (LY 171555), a selective D2 agonist, and the blocking capabilities of spiperone, a selective D2 antagonist. After rats were trained to discriminate 0.025 mg/kg quinpirole from distilled water, a dose-response curve and time course of the quinpirole discriminative stimulus were determined. The effectiveness of three doses of spiperone in blocking the discriminative stimulus produced by 0.02 mg/kg quinpirole was then assessed. Finally, the time course of spiperone's blocking action was determined. Given the putative selective action of these drugs on D2 receptors and the parametric data presented here, it was predicted that following chronic treatment with spiperone, a rebound increase in quinpirole-appropriate responding would occur. Neither chronic treatment with spiperone nor chronic treatment with haloperidol produced the predicted changes. This result, however, may be confined to the specific dose and time parameters used.

Effects on environmentally induced oral stereotypies (object pecking and drinker-directed activity) of preferential antagonists and agonists of adrenoreceptor subtypes were examined in individually caged broiler breeder fowls subjected to chronic food restriction. Three drugs in each category were injected intravenously at three doses, and their effects compared with a saline control treatment. With the antagonists, object pecking was suppressed more by prazosin (alpha 1) and propranolol (beta) than by yohimbine (alpha 2), while drinker-directed activity showed delayed stimulation with yohimbine and propranolol. With the agonists, drinker-directed activity was suppressed more by clonidine (alpha 2) than by isoproterenol (beta) and phenylephrine (alpha 1), while object pecking was inhibited by the high doses of clonidine and isoproterenol but showed delayed stimulation with the low dose of clonidine and (nonsignificantly) the high dose of phenylephrine. Initial suppression of both oral stereotypies by the high doses of yohimbine and isoproterenol, and high and medium doses of clonidine, may have been due to sedation, because in those instances it coincided with increased sitting, an activity not normally seen. Increased standing with clonidine and the medium dose of yohimbine may also reflect sedation. When there were no significant increases in sitting or standing to indicate sedation, responses of both stereotypies were essentially the same with all three adrenoreceptor subtypes; i.e., object pecking was inhibited by the antagonist but not the agonist, while drinker-directed activity was inhibited by the agonist but not the antagonist. It is concluded that alpha 1, alpha 2, and beta adrenoreceptors are all implicated in expression of these stereotypes, and that the two activities may be differentially controlled.

Naloxone's effects on initiation, maintenance, and maximal response effort to acquire food were examined in rats maintained under different levels of food deprivation. In Experiment 1, naloxone was administered SC to rats responding under an FR 80 (first pellet) FR 3 (subsequent pellets) reinforcement schedule. Naloxone did not increase time to acquire the first pellet. Naloxone's suppression of subsequent intake and lowest effective dose were inversely related to level of deprivation. In Experiment 2, rats responded for food under a Progressive Ratio 2 reinforcement schedule. Breakpoint was lowered only when rats were maintained with free access to food. Decreases in response and running rate were inversely related to deprivation level. Results are consistent with the hypothesis that opioids are involved in the maintenance but not the initiation of feeding.

Different forms of food intake are reduced by both agonists and antagonists of dopamine D1 and D2 receptors as well as general opioid antagonists. The present study evaluated whether deprivation (24 h)-induced food intake was altered following systemic administration of either the D1 agonist, SKF-38393, the D1 antagonist, SCH-23390, the D2 agonist, quinpirole, or the D2 antagonist, haloperidol, alone or in combination with the general opioid antagonist, naltrexone. Both SKF-38393 (5-10 mg/kg) and SCH-23390 (100-200 micrograms/kg) significantly and dose dependently reduced deprivation-induced intake. Whereas quinpirole (0.5-1 mg/kg) failed to alter deprivation-induced intake, haloperidol increased deprivation-induced intake at low (50 micrograms) doses and decreased intake at higher (100-500 micrograms/kg) doses. Naltrexone (2.5-10 mg/kg) significantly inhibited deprivation-induced intake. When naltrexone was paired with behaviorally ineffective doses of either SCH-23390 (2.5-100 micrograms/kg), quinpirole (0.01-1 mg/kg), or haloperidol (50 micrograms/kg), the degree of reduction of deprivation-induced intake was significantly greater than that produced by naltrexone alone. Pairing naltrexone with SKF-38393 produced reductions of deprivation-induced intake comparable to that of naltrexone alone.

Rats were tested on days 1, 3, and 5 of a 5-day test week in an operant chamber in which they could either lever press on a fixed-ratio 5 (FR5) schedule to obtain food pellets (Bioserve) or approach and consume lab chow that was also available in the chamber (Teklad Premier). Rats typically pressed at high rates to obtain the food pellets and ate little of the lab chow. On days 2 and 4 of each week lab chow was not concurrently available, and rats could only lever press on the FR5 schedule for pellets to obtain food. Dopamine depletions produced by intraaccumbens injections of the neurotoxic agent 6-hydroxydopamine produced a dramatic decrease in lever pressing and increase in chow consumption on days when lab chow was available. Lever pressing was not significantly reduced in dopamine-depleted rats on days when chow was not available, although there was a significant correlation between lever pressing and accumbens dopamine levels. These results suggest that nucleus accumbens dopamine depletions do not produce a general deficit in food motivation. Moreover, accumbens dopamine depletions do not appear to produce severe deficits in fine motor control that impair the execution of individual motor acts involved in lever pressing. Rather, the present results are consistent with the notion that accumbens dopamine sets constraints upon which food-related response is selected in a particular situation, and that these depletions alter the relative allocation of food-related responses.

In this two-part study, an animal model of binge eating was first produced, then the rate of acquisition of cocaine self-administration was assessed. Initially, 16 female weanling rats were food deprived (DEPR) at 25, 95, and 143 days of age. Another group of 16 age-matched controls was allowed ad lib access to food. Each time the DEPR group was food deprived, they were allowed to recover to normal weight. They were then injected with butorphanol tartrate (BUTR), an opioid that stimulates feeding, and food intake was measured for 4 h. All rats given BUTR consumed significantly more food than those given saline. Animals with DEPR history consumed food over a longer period of time, and at h 4 after BUTR injection, they consumed significantly more food than controls. In the second part of the experiment, an autoshaping procedure was used to quantitatively evaluate the rate of acquisition of cocaine self-administration. By day 30, 86% of the DEPR and 69% of the control groups had acquired cocaine self-administration.

The involvement of CRH and the sympatho-adrenal system in the effects of caffeine on food intake and body weight gain has been investigated in rats. Food intake and body weight gain were measured in male rats after the treatment with caffeine in combination with either an injection of the CRH antagonist alpha-helical CRH(9-41), a surgical adrenal demedullation (medullectomy), or a ganglionic blockade. Alpha-helical CRH(9-41) was injected in the lateral ventricle of the brain and hexamethonium was used to chemically block the ganglionic transmission. From 4 to 24 h following a caffeine injection, spontaneous food intake, which was cumulated from the time caffeine was injected, was significantly (p < 0.01) lower in caffeine- than in saline-treated rats. In food-deprived rats, the anorectic effect of caffeine was biphasic, being significant at 0.5 and 1 h after the caffeine administration, then vanishing for 3 h, and becoming significant again 6 h after the caffeine administration. In both the spontaneously fed and food-deprived rats, caffeine reduced the rate of weight gain, which was measured at the end of a 12- or a 24-h period following the caffeine injection. A significant (p < 0.05) interaction effect of caffeine and alpha-helical-CRH(9-41) was found on the cumulative food intake at 1, 6, and 8 h, and on the amount of food eaten between the 4-6-h interval following the injection of caffeine; the effects of caffeine on food intake and body weight gain seem largely prevented by the use of a CRH antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Bombesin (BBS), a tetradecapeptide, has been found to have potent hypothermic effects when centrally administered. This study was designed to investigate the relationship between food-deprivation and BBS-induced hypothermia in a temperature selection paradigm. Food-deprived and satiated male Sprague-Dawley rats were given intracerebroventricular (ICV) injections of several doses of BBS and control vehicle. Selection temperature data and changes in core body temperature were measured. BBS produced a significant hypothermia and decrease in selection temperatures in all doses but one. No significant differences in body temperature or selection temperatures were found between food-deprived and satiated animals. The results are consistent with the hypothesis that BBS acts centrally to decrease body temperature set point.

In rats made opioid dependent by the implantation of a single morphine 75 mg base pellet, an attempt was made to determine whether any correlational existed between physical and motivational withdrawal signs by adjusting the dose of naloxone used to precipitate withdrawal. The models used to study motivational signs were taste (one- and two-bottle) conditioning and operant responding for food under an FR15 schedule of reinforcement. Naloxone at doses of 0.01 mg/kg and above produced both a conditioned taste aversion (two-bottle test only) and reduced food responding in morphine pellet, but not placebo pellet, implanted animals. No physical withdrawal signs, e.g., wet dog shakes, diarrhoea, were noted until naloxone doses of 0.05 mg/kg and above were used. It is concluded that the difference in naloxone doses required to elicit physical and motivational withdrawal components provides further support for their dissociation.

Functional interactions between serotonergic (5-HT) and opioid drugs have been observed with 5-HT3 receptor antagonism enhancing the inhibitory actions of naloxone and naltrexone in both food-deprived and glucoprivic rats; 5-HT2A/C receptor antagonism enhanced naltrexone's inhibition of insulin hyperphagia. The present study examined whether pretreatment with either general 5-HT (methysergide: 0.5-5 mg/kg), 5-HT2A/C (ritanserin: 0.25-2.5 mg/kg), or 5-HT3 (ICS 205930: 0.5-5 mg/kg) antagonists altered the pattern and magnitude of ad lib intake of simple (sucrose: 10%) or more complex (maltose dextrin: MD, 10%) carbohydrate solutions, or naltrexone's (0.25-2.5 mg/kg) inhibition of these forms of intake. Methysergide significantly increased the pattern and magnitude of sucrose intake at low (0.5-2.5 mg/kg) doses, and transiently delayed the pattern of MD intake at high (5 mg/kg) doses. Ritanserin significantly accelerated the pattern, but not the magnitude of sucrose intake at low (0.25-1.25 mg/kg) doses without affecting MD intake. ICS 205930 reduced the magnitude of sucrose intake at the highest (5 mg/kg) dose, and transiently reduced MD intake. Naltrexone dose dependently altered the pattern and magnitude of both sucrose and MD intake. Coadministration of ritanserin and naltrexone either eliminated or delayed the pattern of opioid antagonist inhibition of both sucrose and MD intake. Methysergide and ICS 205930 pretreatment produced minor changes in the pattern of naltrexone-induced inhibition. These data indicate that 5-HT receptor differentially modulate the pattern of carbohydrate intake, and indicate differential ingestive interactions between 5-HT and opioid antagonists under challenge and palatable conditions.

The effects of various doses of morphine (0, 1.25, 2.5, 5 mg/kg) and clonidine (0, 1.67, 15, 45 micrograms/kg) on motility were determined in food satiated and in food deprived rats. Food deprivation failed to change the general activity of rats after saline injections. Nevertheless, food-deprived animals tested under morphine were more active than food satiated ones. Clonidine exhibited slight psychomotor stimulant properties that were not increased by food deprivation. The results are discussed in terms of possible mechanisms of deprivation-related hypermotility.

Using a two-lever drug discrimination procedure, two groups of four rats each were trained to discriminate the stimulus effects of 1.0 U/kg insulin or 125 mg/kg 2-deoxy-D-glucose (2-DG) from saline. A third group was trained to discriminate food deprivation produced by feeding 23 h prior to sessions from satiation produced by feeding 2 h prior to sessions. Differential responding was a direct function of dose or deprivation level in each group. Rats trained to discriminate insulin responded as if they had received insulin when they received 2-DG and vice versa. Insulin and 2-DG produced deprivation-appropriate responding in two of four rats trained to discriminate food deprivation. Low insulin and 2-DG doses produced drug-appropriate responding in rats deprived 47 h, but not in rats deprived 23 h. Blood glucose level was altered by the training doses of insulin and 2-DG, but not by 23-h deprivation. These results indicate that operations that induce feeding produce discriminable stimuli, and that these effects overlap or interact. Thus, drug discrimination procedures can be useful in the analysis of ingestive behavior.

It has been reported that nursing mother rats can postnatally entrain the circadian rhythms of blinded rat pups, such as locomotor, drinking, and corticosterone rhythms. To gain more insight in the mechanism of the postnatal entrainment of such pups' circadian rhythms, we examined the serotonin N-acetyltransferase (NAT) activity rhythm in blinded rat pups subjected to periodic mother deprivation (PMD) in which mothers were periodically deprived of their pups during either half of a day. We found that only PMD during the light period shifted the phase of NAT activity rhythm in the pups. To cause a reversal of the NAT activity rhythm, it was necessary to repeat PMD for more than 6 days. PMD for 6 h each day also shifted the phase of the blinded rat pups, but it did not reverse the NAT rhythm, even when it was repeated for 10 days. In 9-h deprivation for 10 days, however, deprivation during the first 9 h of the light period reversed the phase, although the latter 9 h failed to cause reversal of the phase. On the other hand, restricted feeding of the mother took more than 11 days to reverse the phase and a foster mother in the cross-fostering experiment failed to affect the phase of pup's rhythm, when the rhythm was determined on the 11th postnatal day. These facts indicate that PMD during the light period is a potent entrainer of the pups' circadian NAT rhythms and provide a useful method of exploring the underlying mechanism of the entrainment of the pups' rhythm by the mother.

In a previous experiment, food deprivation was found to suppress the increase of plasma cortisol and thyroid hormones in stressed animals. Because both the hypothalamo-adrenocortical and the thyroid axes are stimulated during stress, we investigated in this study whether a similar pattern of changes occurs in food-deprived sheep following corticotropin (ACTH) or thyrotropin-releasing hormone (TRH) administration. Each hormone was given as a bolus injection on the fifth day of food deprivation. Blood was sampled by venipuncture five times: 0.5 h before and 1, 3, 5, and 9 h after injection of the hormone. The peak of plasma cortisol in food-deprived sheep following ACTH administration exceeded fourfold the corresponding peak in fed animals. This suggests that food deprivation may enhance the sensitivity of the adrenocortical gland to ACTH and/or reduce binding sites for cortisol in target tissues. In fed animals, TRH was without effect on plasma cortisol level, whereas in food-deprived sheep cortisol transiently increased 2.5-fold, suggesting greater permeability of the blood-brain barrier for TRH. In food-deprived animals, plasma T3 was decreased to 22.6% of basal level, and elevated plasma cortisol after ACTH injection was not able to decrease it further. On the other hand, in fed sheep increased plasma cortisol did decrease plasma T3 as much as 4.2-fold. Circulating T4 was not affected by ACTH treatment. The delta increase of plasma T3 and T4 following TRH administration was comparable in fed and fasted animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent evidence has implicated hypothalamic peptides, such as arginine vasopressin (AVP) and oxytocin (OT) in the control of feeding behavior. In this study, we investigated the impact of food deprivation (48 h) and subsequent refeeding (6 h) on the concentration of AVP and OT in discrete hypothalamic areas, as well as in the neurohypophysis. We also estimated in these rats certain peripheral measures, including hydroelectrolytic parameters, plasma and urine AVP, and plasma corticosterone. The results of this study revealed that food deprivation for 48 h produced little change in OT concentration in the various hypothalamic nuclei studied, including the paraventricular and supraoptic nuclei, with the exception of the median eminence (ME), where a significant decline (-36%; p < 0.05) was detected. This effect was not significantly reversed by 6 h of refeeding. With respect to AVP concentration, food deprivation caused a reliable decline exclusively in the parvocellular subdivision of the paraventricular nucleus (pPVN; -45%; p < 0.01) and in the supraoptic nucleus (SON; -45%; p < 0.01). No change in AVP was detected in the ME or in most other hypothalamic nuclei examined. Refeeding for 6 h actually potentiated the effect of food deprivation, decreasing further from baseline the content of AVP in the pPVN and SON. The only other hypothalamic area to exhibit a change in AVP content was the ventromedial nucleus, where AVP level increased (p < 0.001) after deprivation and declined to normal after 6 h of refeeding. The content of AVP and OT in the neurohypophysis was unaffected by food deprivation and subsequent refeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

The study investigated the relationship between the behavioural response to a standard dose of amphetamine and environmentally induced stereotypies in pigs. There were large individual differences in the frequency of amphetamine-induced stereotypies and time spent in locomotion. In addition, these two measures tended to be negatively correlated to each other, indicating that they were competitive. Levels of amphetamine stereotypies were negatively correlated with those of chain manipulation and drinking after a period of 50 and 100 days of physical restraint and food restriction; levels of locomotion were positively correlated with levels of chain manipulation after 100 days of restraint and restrictive feeding. These results suggest that pigs differ in their predisposition to develop environmentally induced stereotypies, and that this is related to catecholaminergic systems in the brain. In an amphetamine test performed after the period of restraint and restrictive feeding, amphetamine stereotypies were generally higher than in the first test but behaviour was no longer correlated to previous levels of environmentally induced stereotypies. The qualitative differences between the two forms of stereotypy, their negative rather than positive correlation, and the lack of correlation between environment-dependent stereotypies and stereotypies in the second amphetamine test suggests a complex relationship between these two forms of stereotypies. The increased amphetamine sensitivity in the second amphetamine test may reflect the effect of stress on central catecholaminergic systems.

Norepinephrine (NE), acting through alpha 2-noradrenergic receptors in the hypothalamic paraventricular nucleus (PVN), has been implicated in the control of feeding behavior and body weight gain. To determine whether this hypothalamic receptor system is disturbed in genetically obese rats, the binding of radioligands to alpha 2-noradrenergic, as well as to alpha 1-noradrenergic, receptors was examined in seven hypothalamic nuclei of obese Zucker rats relative to their lean littermates. Receptor binding procedures, using the alpha 2-noradrenergic agonist [3H]p-aminoclonidine ([3H]PAC) and the alpha 1-noradrenergic antagonist [3H]prazosin, demonstrated that the obese rats, compared to the lean rats, had significantly greater alpha 2-noradrenergic and alpha 1-noradrenergic receptor binding, specifically in the PVN as opposed to other hypothalamic areas examined. Moreover, the obese rats, compared to the lean rats, exhibited greater responsiveness to the effects of food deprivation (48 h), which caused a significant decline in radioligand binding to both alpha 2 and alpha 1 receptors, specifically in the PVN. A decrease in alpha 2-receptor binding after deprivation in the obese rats was also seen in two basal hypothalamic areas, namely, the supraoptic nucleus and arcuate nucleus-median eminence. The possibility exists that these disturbances in hypothalamic alpha-receptors may be involved in the development and/or maintenance of the genetic obesity.

A group of female rats was deprived and maintained at 75-80% of body weight at three different times during development. Following recovery to normal weight, food intake was measured with and without butorphanol tartrate, a kappa-sigma agonist, 8 mg/kg SC. Animals with a history of deprivation (DEP) showed an increase in postrecovery feeding when they were tested at normal body weight and not food deprived. More importantly, butorphanol prolonged food intake in the 3-h eating test only in the rats with a developmental history of food restriction. A developmental history of fasting in eating disorders may trigger changes in opiate systems that result in atypical feeding behavior in the adult.

Food restriction, combined with access to a running wheel, produces "activity anorexia" (self-starvation) in rats. The relative effects of ethanol and propylene glycol on activity-maintained self-starvation were examined. Young male rats were provided with access to a running wheel while on a 22.5-h food deprivation schedule. One-third were concurrently provided with a 7% solution of ethanol, one-third with a (pharmacologically weak) 7% solution of propylene glycol, and one-third with water. Results indicated that neither survival rate nor running activity were affected significantly by ethanol consumption, relative to water-drinking controls. However, increased survival rates and decreased activity were observed for those animals which consumed propylene glycol. Antagonistic effects of ethanol on energy metabolism, stress responses, and the preservation of body weight are considered in light of these findings.

Whereas opiate receptor antagonists generally act to inhibit food intake under a variety of physiological conditions in rats, agonists of some serotonin (5-HT) receptor subtypes appear to stimulate intake, and others appear to inhibit intake. The present study evaluated the effects of the general 5-HT receptor antagonist, methysergide (1-5 mg/kg), the 5-HT2 receptor antagonists, ketanserin (1-2.5 mg/kg) and ritanserin (1-2.5 mg/kg), and the 5-HT3 receptor antagonist, ICS 205930 (1-5 mg/kg) upon deprivation (24 h)-induced intake themselves, and upon the hypophagic properties of the general opiate receptor antagonist, naloxone (1-5 mg/kg). Whereas the high doses of methysergide (0.5-4 h, 34%) and ketanserin (0.5 h, 28%) significantly decreased deprivation-induced intake themselves, ritanserin and ICS 205930 were without effect. Naloxone produced dose-dependent reductions in deprivation-induced intake (24-45%). Methysergide (1 mg/kg) significantly potentiated naloxone (5 mg/kg) hypophagia after 0.5 h. Significant potentiations of hypophagia occurred following pairing the 1 mg/kg ketanserin dose with the 1 and 5 mg/kg naloxone doses at 2 and 4 h respectively, and pairing the 2.5 mg/kg ketanserin and 1 mg/kg naloxone doses at 0.5 and 2 h. Whereas the 1 mg/kg dose of ritanserin eliminated naloxone (1 mg/kg) hypophagia over a 2-h time course, ritanserin failed to exert further effects in other dose conditions. The differences between ketanserin and ritanserin in their effects upon deprivation-induced feeding and naloxone hypophagia suggest that the former's antagonistic actions upon alpha-adrenergic receptors may be responsible for its effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Phencyclidine (PCP) sensitivity of rats, whose body weights were maintained at 70% of free-feeding controls, was compared to drug sensitivity of the controls in terms of unconditioned (exploratory) behavior and plasma corticosterone levels. Low doses of PCP HCl [0 (saline vehicle), 0.3 or 0.9 mg/kg, SC] were given to food-deprived rats and to free-feeding controls 15 minutes before measuring unconditioned behavior for 90 minutes; then PCP in brain and corticosterone in plasma were assayed. An additional group (0.43 mg/kg) was established from the reduced-weight rats in order to compare with free-feeding rats given 0.3 mg/kg, the same absolute dose-a circumstance reflecting "street" usage in which doses are not adjusted for body weight differences among users. These low doses of PCP altered exploratory behaviors, but there did not appear to be an interaction between food-deprivational status and drug, with the possible exception of an altered effect of PCP upon habituation in the lighter animals. PCP elevated plasma corticosterone levels over saline controls only in the reduced-weight rats. The drug, possibly reflecting a tranquilizing action of the lowest dose, reduced corticosterone levels in free-feeding controls. Brain levels of drug were directly related to dose, and were elevated in the food-deprived animals 26-30% over those at the same per-weight dose levels in the free-feeding rats, in spite of being given lower absolute amounts of drug. In the 0.43 mg/kg reduced-weight dose group, given the same absolute dose as the 0.3 mg/kg free-feeding group, brain levels were doubled over the latter group, and exploratory behavior was correspondingly different from the free-feeding group.(ABSTRACT TRUNCATED AT 250 WORDS)

Tritium-labelled phencyclidine (PCP) hydrochloride (12 mg/kg) was injected SC for six consecutive days into two groups of eight male rats maintained at 85% of their initial free-feeding weights. Eight days after the last injection, electric footshock raised fat levels of PCP 28% over nonshocked controls, and lowered blood levels 18%, but did not alter brain levels of the drug significantly. Thus, application of an acute stressor does result in redistribution of tissue stores of phencyclidine as predicted in the literature; however, the direction of the redistributions was to fat, rather than to brain. To explore the relation of a long-term stressor (one that eliminates adipose tissue as a sink for mobilized PCP), exploratory behavior was evaluated in male rats during six days of food deprivation commencing after six daily injections of PCP HCl (2 or 4 mg/kg, SC). Exploratory behavior of the 4 mg/kg dose group was abruptly altered, compared to saline controls, at six days of food deprivation, when the rats' body weights were about 70% of initial weights and when body fat would be severely reduced or depleted. To assess replicability and generalizability of this phenomenon, PCP HCl (4 or 8 mg/kg, SC) or dextroamphetamine sulfate (3.2 or 6.4 mg/kg, SC) was injected into male rats for six days and food deprivation followed afterward for nine consecutive days, or until similar body weight reductions as in the first experiment were achieved. Again, exploratory behavior was altered in comparison to saline controls in phencyclidine-treated rats (at the 4 mg/kg dose level) when rats reached about 70% of initial weights.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the effects of catecholaminergic drugs on independent feeding during development, preweanling rats were administered amphetamine (AMPH) or chlorpromazine (CPZ) and were allowed to ingest milk through anteriorly located intra-oral cannulas. In 1-hr milk-deprived rat pups, AMPH stimulated milk intake at 3, 7 and 10 days of age and suppressed intake at 15 days. In 22-hr-deprived pups, AMPH had no effect at 3, 7 and 10 days, but reliably suppressed intake at 15 days. CPZ stimulated intake in 3-, 10- and 15-day-old milk-satiated pups. In 22-hr-deprived pups, CPZ had no effect at 3 and 10 days, but stimulated intake at 15 days. While AMPH produced pronounced nonappetitive behavioral activation in conjunction with enhanced intake in 1-hr-deprived pups, AMPH-induced activation occurred without enhanced intake in 22-hr-derived pups. Thus, there was a dissociation between AMPH's effect on milk intake and AMPH-induced nonappetitive behavioral activation. Collectively, the present results support the following conclusions. First, a catecholaminergic system(s) that enhances independent feeding is present very early in postnatal development of the rat. Second, level of food deprivation is an important state-dependent variable when assessing the effects of AMPH and CPZ on independent feeding in preweanling rats.

Mode of action of clonidine involved in self-injurious behavior was assessed in mice. Single injection of clonidine (50 mg/kg, IP) evoked a self-biting which occurred more frequently under the condition of isolation and food-deprivation for 24 hr. The clonidine-induced self-biting was not reduced, but rather potentiated by pretreatment with phentolamine (10 mg/kg). This behavior was enhanced by theophylline (20 mg/kg) but was inhibited to some extent by adenosine (10 mg/kg) or dipyridamole (10 mg/kg). In addition, the self-injurious behavior was completely antagonized by combined pretreatment with adenosine (10 mg/kg) and dipyridamole (10 mg/kg), and by potent adenosine agonists, such as N6-(L-phenylisopropyl) adenosine (0.2 mg/kg) and N6-cyclohexyladenosine (0.2 mg/kg). These results, therefore, suggest that the clonidine-induced self-biting could be substantially attributed to adenosine A1-receptor blockade as documented for pharmacological property of theophylline in the brain.

The effects of 24 hours of food deprivation on the subjective response to 10 mg oral d-amphetamine were studied in 12 healthy normal volunteers. A within-subjects design was used in which subjects ingested amphetamine and placebo capsules in both a fed and a fasting state. Each of the four experimental conditions-FED/DRUG, FED/PLACEBO, FAST/DRUG, FAST/PLACEBO--was enacted twice according to a randomized block design. Three subjective effects questionnaires, the Profile of Mood States, the Addiction Research Center Inventory, and the Visual Analogue Scale, were completed prior to and 1, 3 and 6 hr after the early morning capsule ingestion. Typical elevations in such subjective effects as elation and vigor were obtained after amphetamine ingestion in both feeding conditions, but fasting neither potentiated nor attenuated the drug response. Subjects at the end of the session, however, were more likely in the FAST/DRUG condition than in the FED/DRUG condition to label the capsule they had ingested at the beginning of the session as a stimulant.

One group of free-feeding rats was given a 5 microgram/ml etonitazene HCl solution as their sole liquid. This group increased their drug intake by 100% when they were partially food-deprived during a 23-day period. Another group that remained food-satiated and received etonitazene for an equal number of days did not show similar increases in drug intake. However, this group drank greater volumes of the etonitazene solution than a food-satiated control group drank of water. These results are contrasted with a fourth group showing a 50% decrement in water intake during similar food-deprived conditions. The food-deprived group drinking etonitazene showed highly erratic drinking patterns compared to all the other groups. Daily liquid intake ranged from 30 to 250 ml in this group, and volumes oscillated from high to low on alternating days. When the food-deprived/food-satiated conditions were replicated in this experimental group, corresponding increases and decreases in drinking reliably occurred. However, during the second food-deprived phase, the large increases occurred almost immediately as contrasted with a gradual increase over 17 days during the first food-deprived phase. This would suggest a learning mechanism may be involved. Self-mutilation and other forms of stereotypy were noted only in food-deprived rats consuming etonitazene.

During the course of studies of the effects of pantethine, a cysteamine precursor known to deplete tissue concentration of immunoreactive somatostatin, we observed that the subject rats continued to eat despite marked distension of the stomach. To determine whether this effect was caused by drug-altered food intake, we have measured food and water intake in pantethine-injected rats in the fed and fasting state. In three separate experiments, rats allowed free access to food until the morning of study showed significant increased food intake accompanied by an increased stomach content (at 4 hr) of both food and water following the IP injection of pantethine. In one experiment, intake at 3 hours was 0.60 g/100 g b.wt. (pantethine dose 0.74 g/kg b.wt.) and 0.64 g/100 g b.wt. (pantethine dose 1.47 g/kg b.wt.) compared with 0.24 g/100 g b.wt. in saline-treated animals (p less than 0.05). In contrast, pantethine, 1.47 g/kg b.wt., when administered to overnight-fasted rats, significantly inhibited food intake (3-hr intake 1.54 +/- 0.16 g/100 g b.wt. in rats injected with pantethine 1.47 g/kg b.wt. as compared with 3.3 +/- 0.21 g/100 g b.wt. in saline-injected controls). The intake-stimulating effect of pantethine in ad lib-fed rats was not demonstrable when the drug was administered shortly before the "lights out"-induced feeding at night. These findings indicate that pantethine, a cysteamine precursor, stimulates food intake in satiated rats, depending upon the stage of circadian rhythm, but is inhibitory to intake in fasted animals. We postulate that the effects are mediated directly or indirectly through the disinhibition of central appetite-regulating somatostatinergic pathways but, since cysteamine also inhibits dopamine-beta-hydroxylase, an effect on depletion of appetite-regulating central catecholamines cannot be excluded.

Intraperitoneal administration of the opiate antagonist, naloxone hydrochloride, resulted in decreased food and water consumption in drug-naive cats. In a cross-over Latin Square design, food consumed by six cats in a one hour period following 23 hours of deprivation, was decreased significantly below control (p less than 0.05) in linear relation to increasing dose (1 mg/kg and 10 mg/kg) of naloxone. Non-linear and time/order effects were not significant. Water consumption was decreased below control in a linear relation to increasing dose (1 and 10 mg/kg) for 5 of 6 cats at the 0.05 significance level. Non-linear and time/order effects on water consumption were not statistically significant for the same 5 cats. These results, and behavioral signs (i.e., vomiting, persistant vocalization, heavy salivation, mydriasis, moderate catatonia, and hissing) occasionally exhibited by four of the six cats in a 1-hr period following injection of the high dose, suggest a malaise-effect of naloxone.

The effects of 1.0, 3.0 and 5.0 g/kg of ethanol on blood glucose levels and body temperature were examined in rats submitted to either acute food deprivation (24 or 48 hr), chronic starvation, or to both chronic plus acute food deprivation. The results show that: (a) 3.0 and 5.0 g/kg produced either an increase or a decrease of glucose levels depending on the state of fasting; (b) rats not deprived of food presented hyperglycemia while being hypothermic; (c) a marked hypothermia was present when no substantial alterations in glycemia were observed; and (d) in cases where hypoglycemia and hypothermia occurred, the fall in body temperature paralleled or preceded the decrease in glucose levels.

Deermice, subjected to food rationing and low ambient temperature, were sacrificed in normothermia or during daily torpor. Levels of monoamines and their metabolites in the caudate putamen (CPN), the suprachiasmatic nuclear area (SCN), and the median raphe nucleus (MRN) were quantified through the use of HPLC with electrochemical detection. Significant elevations in levels (pg/mg protein) of the serotonin (5-HT) metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) were noted in torpid individuals in all nuclei examined. The dopamine (DA) metabolite, homovanillic acid (HVA) was significantly elevated in the CPN and MRN of torpid individuals. Moreover, a significant increase in the HVA to DA ratio was also noted in the CPN and the MRN. In the SCN, the concentrations of 5-hydroxytryptophan (5-HTP), 5-HT, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were also increased significantly during torpor. These significant elevations suggest that an increase in the activity of the serotonergic and dopaminergic systems occurs in these nuclei during daily torpor in the deermouse.

Serum barbiturate levels were tracked for several hours in food deprived rats given 40, 60 or 80 mg/kg (SC) of either phenobarbital or barbital. All 3 phenobarbital doses produced peak serum drug levels at 1.5 hr postinjection. Serum barbital concentrations peaked 3 hr after both 60 and 80 mg/kg barbital doses while the 40 mg/kg dose produced a stable low drug level throughout the 4 postinjection hours. For both barbiturates administered, 40 mg/kg doses produced lower serum drug levels than either 60 or 80 mg/kg. The differences in serum drug concentrations between the latter two dose levels were inconsistent over time.